Abstract
Nitric oxide (NO) can stabilize mRNA by activating
p38 mitogen-activated protein kinase (MAPK). Here,
transcript stabilization by NO was investigated in
human THP-1 cells using microarrays. After LPS
pre-stimulation, cells were treated with actinomycin
D and then exposed to NO without or with the p38
MAPK inhibitor SB202190 (SB). The decay of 220
mRNAs was affected; most were stabilized by NO.
Unexpectedly, SB often enhanced rather than antagonized
transcript stability. NO activated p38
MAPK and Erk1/2; SB blocked p38 MAPK, but
further activated Erk1/2. RTPCR confirmed that
NO and SB could additively stabilize certain mRNA
transcripts, an effect abolished by Erk1/2 inhibition.
In affected genes, these responses were associated
with CU-rich elements (CURE) in 30-untranslated
regions (30-UTR). NO stabilized the mRNA of a
CURE-containing reporter gene, while repressing
translation. Dominant-negative Mek1, an Erk1/2
inhibitor, abolished this effect. NO similarly stabilized,
but blocked translation of MAP3K7IP2, a
natural CURE-containing gene. NO increased
hnRNP translocation to the cytoplasm and binding
to CURE. Over-expression of hnRNP K, like NO,
repressed translation of CURE-containing mRNA.
These findings define a sequence-specific mechanism
of NO-triggered gene regulation that stabilizes
mRNA, but represses translation.
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